ABT-378/ritonavir in Treatment-Experienced-- 48-Weeks Follow-Up

10th Report from: 7th Conference on Retroviruses and Opportunistic Infections, San Francisco, Wednesday Feb 2

ABT-378/ritonavir in Treatment-Experienced-- 48-Weeks Follow-Up

S. DEEKS*^{1}, S. BRUN^{14}, Y. XU^{14}, K. REAL^{14}, C. BENSON^{2}, H. KESSLER^{3}, R. MURPHY^{4}, D. WHEELER^{5}, C. HICKS^{6}, J. ERON^{7}, J. FEINBERG^{8}, R. GULICK^{9}, P. SAX^{10}, R. STRYKER^{11}, S. RIDDLER^{12}, M. THOMPSON^{13}, M. KING^{14}, A. POTTHOFF^{14}, A. HSU^{14}, R. BERTZ^{14}, A. MOLLA^{14}, H. MO^{14}, D. KEMPF^{14}, A. JAPOUR^{14}, and E. SUN^{14} for the M97-765 Study Group. ^

{1}Univ. of California, San Francisco; ^{2}Univ. of Colorado Hlth. Sci. Ctr., Denver; ^{3}Rush Med. Coll., Chicago, IL; ^{4}Northwestern Univ., Chicago, IL; ^{5}Inf. Dis. Physicians; ^{6}Duke Univ., Durham, NC; ^{7}Univ. of North Carolina at Chapel Hill; ^{8}Univ. of Cincinnati, OH; ^{9}Cornell Univ., New York, NY; ^{10}Harvard Univ., Boston, MA; ^{11}Pacific Oaks Res.; ^{12}Univ. of Pittsburgh, PA; ^{13}AIDS Res. Consortium of Atlanta, GA; and ^{14}Abbott Labs., Abbott Park, IL.

Updated information was reported on ABT-378 at this conference on its use in both treatment-naÔve individuals and for those with treatment experience. This new PI is co-formulated with low-dose ritonavir, an inhibitor of cytochrome P450. Ritonavir inhibits the activity of P450 which has the result of increasing the blood levels of other drugs. In the case of its use with ABT-378 ritonavir enhances the pharmacokinetic profile of ABT-378, essentially meaning it increases the blood levels of ABT-378 making 378 more potent. For use in phase 3 clinical trials the dose selected is 400 mg ABT-378/100 mg ritonavir bid (twice daily). Its co-formulated as 3 capsules bid. The authors of abstract at conference said ABT-378 Cmin/EC50 ratio for wild-type HIV is >30, potentially providing a pharmacological barrier to the emergence of viral resistance and activity against resistant virus. This report describes the data from the study in treatment-naives. In a 2^nd report which will follow I will describe the new data reported on ABT-378s use in treatment-naive. The authors also said the Cmin/EC50 ratio for currently available PIs is equal to or less than 4 fold, based on EC50 values determined in the presence of 50% human serum.

To qualify for study individuals had to have between 10,000 and 100,000 copies/ml viral load and the baseline median was 10,000 copies/ml. Median baseline CD4s were 349. They had to be on treatment with one PI and 2 NRTIs for 3 or more months at study entry; naÔve to at least one NRTI, no prior NNRTI experience. And experience only with the PI they are currently on. No prior PI experience was permitted. The PI experience patients had prior to study were: indinavir (44%); nelfinavir (36%), saquinavir (13%), ritonavir (6%), amprenavir (1%). 3TC was the most common NRTI used at baseline (87%), followed by d4T (56%), and AZT (43%), and ddI (10%).

Seventy patients were randomized to receive ABT-378/r (400/100 mg/bid or 400/200 mg bid) in place of their current PI, in combination with their existing NRTIs. On day 15 of study, nevirapine (200mg once daily for 14 days then 200 mg bid) was added and NRTIs were changed to include at least one which was new to the patient.

Baseline Viral Susceptibility

PI phenotypic susceptibility data were available for 57/70 baseline viral isolates (VIRCO Antivirogram method). Baseline viruses from 63% of patients (36/57) displayed a 4 or greater fold loss in susceptibility to the previous PI, and 32% of patients (18/57) had viruses with 4 or greater fold loss to 3 or more protease inhibitors. Of 56 patients for whom baseline phenotype for all the drugs in the previous regimen was available, the incidence of 4 or more fold change in EC50 (reduced sensitivity or susceptibility) to one, two, or three previous drugs was 20% (36%), 25 (45%), and 9 (16%), respectively. Nineteen percent of patients (11/57) had 4 or more fold reduction in susceptibility to ABT-378 at baseline.

Results

On Treatment analysis: 86% (48/56) had viral load <400 copies/ml, 76% (41/54) <50 copies/ml at week 48
Intent-to-treat analysis: (ITT M=F; missing values (M) considered as treatment failures (F): 70% (49/70) had VL <400, and 60% (42/70) had <50 copies/ml at week 48
Authors reported that of the 11 patients with 4 or more fold reduced susceptibility to ABT-378, 7 had VL <400 copies/ml at week 48
Viral suppression was rapid with a marked HIV-RNA reduction during the first two weeks of therapy, prior to the addition of nevirapine. VL decline through week 2 was independent of prior PI experience and EC50 of ABT-378 against baseline viral isolates
Mean CD4 count at week 48 was 504 (mean increase of 125)

Tolerability

The most common drug-related adverse events were diarrhea and asthenia. Twelve patients discontinued the study through 48 weeks; of these only 3 discontinuations were due to adverse events related to study drug.

Most Common Adverse Events and Lab Abnormalities

Diarrhea 21% (15/70)*
Asthenia 6% ( 4/70)*
Grade 3/4 lab abnormalities
GGT (>5xULN) 26% (18/70)
Total Chol. (>300 mg/dL) 25% (17/70)
Trigyc. (750 mg/dL) 25% (17/70)
AST/ALT (>5xULN) 16% (11/70)

* events of at least moderate severity and probable, possible or unknown relationship to ABT-378 are included

Patient Disposition

Of the 70 patients enrolled 12 discontinued at or before 48 weeks. Three were reported to be due to study drugs--nausea/vomiting/flatulence/diarrhea (1), rash (1), diarrhea (1). Other reasons for discontinuation are 1 person had myocardial infarction on day one of study, 2 for personal reasons, 2 deaths (metastatic lung carcinoma, rhabdomyolysis with acute renal failure), 2 for non-compliance, and 2 lost to follow-up.